The present invention relates to blood cleansing in general and, more particularly, to diafiltration systems.
Hemodiafiltration combines standard dialysis and hemofiltration into one process, whereby a dialyzer cartridge containing a high flux membrane is used to remove substances from the blood both by diffusion and by convection. The removal of substances by diffusion is accomplished by establishing a concentration gradient across a semi-permeable membrane by flowing a dialysate solution on one side of the membrane while simultaneously flowing blood on the opposite side of the membrane. To enhance removal of substances using hemodiafiltration, a substitution fluid is continuously added to the blood either prior to the dialyzer cartridge (pre-dilution) or after the dialyzer cartridge (post-dilution). An amount equal to that of the substitution fluid is then ultrafiltered across the dialyzer cartridge membrane carrying with it additional solutes.
Substitution fluid is usually purchased as a sterile/non-pyrogenic fluid contained in large flexible bags or is produced by on-line filtration of a non-sterile dialysate through a suitable filter cartridge rendering it sterile and non-pyrogenic. Such on-line production of substitution fluid is described, inter alia, in D. Limido et al., xe2x80x9cClinical Evaluation of AK-100 ULTRA for Predilution HF with On-Line Prepared Bicarbonate Substitution Fluid. Comparison with HD and Acetate Postdilution HFxe2x80x9d, International Journal of Artificial Organs, Vol. 20, No.3 (1997), pp. 153-157.
In general, hemodiafiltration schemes use a single dialyzer cartridge containing a high flux semi-permeable membrane. Such a scheme is described, for example, in P. Ahrenholz et al., xe2x80x9cOn-Line Hemodiafiltration with Pre- and Postdilution: A comparison of Efficiencyxe2x80x9d, International Journal of Artificial Organs, Vol. 20, No.2 (1997), pp 81-90 (xe2x80x9cAhrenholz et al.xe2x80x9d). Substitution fluid is introduced into the blood stream either in a pre-dilution mode or in a post-dilution mode relative to the dialyzer cartridge. The preferred mode for maximal removal of both small and large substances from blood is the post-dilution mode, which achieves the highest concentration gradient between the blood and the dialysate fluid. In a typical pre-dilution mode with on-line generation of the substitution fluid, however, the bloodside concentration is lowered relative to the dialysate fluid. As a result, removal (or clearance) of substances can decrease, as described in Ahrenholz et al. This is particularly true for smaller molecules like urea, whereby mass transport is driven more by the diffusion process than by the convection process.
A hemodiafiltration scheme using first and second dialyzer cartridges is described in J. H. Miller et al., xe2x80x9cTechnical Aspects of High-Flux Hemodiafiltration for Adequate Short (Under 2 Hours) Treatmentxe2x80x9d, Transactions of American Society of Artificial Internal Organs (1984), pp. 377-380. In this scheme, the substitution fluid is reverse-filtered through a membrane of the second dialyzer cartridge with simultaneous filtration of fluid across a membrane in the first dialyzer cartridge. Counter-current flow of dialysate occurs at both cartridges.
Certain trade-offs exist with respect to removal of different size molecules when comparing pre-dilution diafiltration and post-dilution diafiltration using a single dialyzer cartridge. For example, with on-line pre-dilution diafiltration, one can achieve higher convective filtration rates (compared to on-line post-dilution diafiltration) to enhance removal of large molecules, however, this comes at the expense of reducing the removal of small molecules like urea and creatinine. In on-line post-dilution diafiltration, however, only a limited amount of fluid can be filtered from the blood as it passes through the dialyzer cartridge. The filterable amount is dependent upon several factors, including blood flow rate, blood hematocrit and blood protein concentration. Typically, the filterable amount is 20% to 30% of the incoming blood flow, depending on blood flow rate. For example, at a blood flow rate of 300 ml/min, the filterable amount is limited to about 90 ml/min. Additionally, in on-line pre-dilution or post-dilution diafiltration, there is some loss in clearance due to the lower dialysate flow rate through the diafilter cartridge. For example, at a nominal dialysate flow of 500 ml/min, when 100 ml/min is used as an on-line source of substitution fluid, the resultant dialysate flow into the diafilter cartridge is 400 ml/min.
It is an object of the present invention to provide a hemodiafiltration method and a device which overcome the limitations associated with convection filtration in existing on-line post-dilution schemes. It is also an object of the present invention to reduce the loss of small molecule clearance associated with on-line pre-dilution diafiltration using a single dialyzer cartridge. In accordance with the present invention, clearance is improved by introducing a non-isosmotic fluid to the dialysate fluid stream and optionally to the substitution fluid stream.
The present invention may be embodied in an improved dialysis machine, e.g., a dialysis machine which is adapted to perform improved hemodiafiltration in accordance with the invention. Alternatively, the hemodiafiltration device of the present invention may be embodied in an xe2x80x9cadd-onxe2x80x9d system which may be used in conjunction with a standard UF controlled dialysis machine to perform improved hemodiafiltration.
A hemodiafiltration device in accordance with an embodiment of the present invention includes at least one dialyzer (e.g., a dialyzer cartridge) for diafiltration, at least one sterility filter (e.g., a sterility filter cartridge) for generating a sterile substitution fluid, a non-isosmotic fluid supply, and a control unit which controls fluid inputs and outputs between the at least one dialyzer, the at least one sterility filter cartridge, the non-isosmotic fluid supply and the dialysis machine.
The dialyzer may contain a semi-permeable membrane which may be embedded within a jacket or housing of a dialyzer cartridge. The membrane separates the dialyzer into a blood compartment and a dialysate compartment. In an embodiment of the present invention, at least first and second dialyzers are used to carry out the diafiltration process. The first and second dialyzers may include first and second dialyzer cartridges or a single cartridge having first and second dialyzer sections. The at least one sterility filter may contain semi-permeable membranes and may be used to remove bacteria, endotoxins, and other particulate from the dialysate, thereby generating a suitable substitution fluid stream on-line. The control unit may contain various pumps, pressure monitoring devices, valves, electronic components, connector fittings, tubing, etc., as required in order to coordinate the operation of the other system components.
Blood enters the bloodside compartment of the first dialyzer, whereby some plasma water is filtered across the semi-permeable membrane into the adjacent dialysate compartment. As the blood leaves the first dialyzer, substitution fluid is added to the blood at a rate higher than the rate at which plasma water is filtered out of the first dialyzer. In accordance with an embodiment of the present invention, the substitution fluid may include a non-isosmotic substitution fluid.
The diluted blood then enters the bloodside compartment of the second dialyzer, whereby additional plasma water (equal to the excess amount of substitution fluid) is filtered across the semi-permeable membrane and into the adjacent dialysate compartment. In this manner, the substitution fluid acts as a post-dilution fluid relative to the first dialyzer as well as a pre-dilution fluid relative to the second dialyzer.
An advantage of this process is that a gain in clearance of small molecular weight substances in the first dialyzer overshadows a loss in clearance of small molecular weight substances due to the dilution of blood concentration entering the second dialyzer. Further, clearance of larger molecular weight substances is enhanced considerably, because the total filtration level of plasma water is practically doubled (e.g. 40% to 80% of the incoming blood flow rate may be filtered) compared to filtration using a single dialyzer operating in a post-dilution mode.
The dialysate fluid may be generated by the dialysis machine. Preparation of the dialysate solution may include mixing of water with dialysate concentrate. Using a water preparation module, a supply of water may be pre-treated, e.g., by heating and/or degassing or using any other pre-treatment method known in the art. A dialysate preparation module, as is known in the art, may be used to supply dialysate concentrate to obtain suitable proportioning of dialysate to water.
When two dialyzers are used, the dialysate fluid may enter the second dialyzer cartridge and run counter-parallel to the blood flow direction. In accordance with an embodiment of the present invention, the dialysate preparation module produces non-isosmotic or isosmotic dialysate fluid. The dialysate fluid acts to provide a concentration gradient against the bloodside fluid thereby facilitating the diffusion of solutes across the semi-permeable membrane. As the dialysate traverses through the dialysate compartment, the dialysate flow rate increases due to plasma water filtering across into the dialysate compartment as mentioned above. Upon exiting the second dialyzer cartridge, the dialysate fluid may be pumped into the first dialyzer cartridge, again running counter-parallel to the bloodside fluid. At this point, a non-isosmotic dialysate fluid may be added to the dialysate fluid, resulting in fluid which is either hypertonic or hypotonic relative to the blood. The addition of this fluid may have the following effects: (a) an increase in the overall dialysate flow results in a reduction of the dialysate side-mass transport resistance; (b) a reduction in the dialysate inlet solute concentration prior to entering the first dialyzer cartridge results in an increase of the concentration gradient across the semi-permeable membrane; (c) a fluid shift across the red blood cell membrane further enhances transport of solutes out of the red blood cells; and (d) larger molecules sieved by the red blood cell membrane are trapped in the plasma water space thus increasing their concentration gradient relative to the dialysate. In some embodiments of the invention, pre-treated water is used as the non-isosmotic fluid added to the dialysate fluid. This may have the added benefit of increasing dialysate flow without increasing costs associated with the amount of dialysate concentrate being used.
The dialysate flow rate increases as it traverses through the dialysate compartment again, due to filtration of plasma water across the semi-permeable membrane. Upon exiting the dialyzer cartridges, the used dialysate is transported back to the dialysis machine. A dialysate pump may be placed between the first and second dialyzers. The pump may be used to control the relative amount of plasma water filtered across the membranes of the two dialyzers.
Preparation of the sterile/non-pyrogenic substitution fluid may be performed by drawing a portion of fresh dialysate solution from a dialysate inlet line and pumping it through the sterile filter cartridge. Water from the water preparation module may be added to the dialysate, such that the substitution fluid becomes hypotonic before it is infused into the blood stream. The sterile filter cartridge may perform multiple filtration of the dialysate solution, e.g., using a plurality of filtration cartridges or a plurality of filtration sections in a single cartridge, before introducing the dialysate into the blood stream as substitution fluid. This enhances safety, e.g., should one of the filters fail during treatment.
To ensure that the blood does not become diluted or over-concentrated as it passes through the dialyzer cartridges, control of filtration may be accomplished by use of two independent fluid balancing systems and a separate UF pump. A main balance system may regulate the overall dialysate flows, while a secondary balance system may be used to balance dialysate flows that are offset by the addition of a second fluid stream to the dialysate circuit as part of the non-isosmotic flow streams. To ensure that the blood being cleaned returns substantially to its original osmotic state before going back to the patient, the primary dialysate fluid may be isotonic, slightly hypertonic, or slightly hypotonic, depending on the nature of the second dialysate fluid. Pressures may be monitored both on the bloodside and dialysate side of each dialyzer cartridge as a means to determine transmembrane pressure (TMP) across each of the dialyzers.